The overall objective of this proposal is to develop a novel in vivo optical imaging system that will quantify structural biomarkers of retinal degenerative diseases. The state-of-the-art technology is measurement of the thickness of retina layers by spectral domain optical coherence tomography (SDOCT). However, while SDOCT can resolve histological layers, it lacks the resolution to measure cellular features. In recent SDOCT studies, only a modest correlation between the thickness of the retinal nerve fiber layer and the progression of glaucoma has been shown, with similar findings seen between the thickness of the photoreceptor layer and progression of retinitis pigmentosa. This reflects the fact that thickness of an individual retina layer does not necessarily correlate with the healt or anatomical condition of its constituent cells. We have shown that angle-resolved low coherence interferometry (a/LCI), a light scattering method that incorporates the depth resolution of OCT, can acquire depth-resolved morphological measurements of esophageal epithelial cells, which allows in vivo early detection of dysplasia in Barrett's Esophagus patients Unlike other non-invasive imaging techniques, a/LCI allows direct and specific measurements of the nuclear morphology of epithelial cells within intact, unstained tissues. We have shown that a/LCI can detect changes in organization of cells in the retinal layer due to pathology. We now propose to apply a/LCI to the diagnosis of ocular diseases by developing an a/LCI imaging system that is compatible with a scanning ophthalmoscope in order to execute depth-resolved measurements of the nuclear morphology of retinal neurons. Here we will seek to formulate accurate quantitative biomarkers that predict the onset and progression of neurodegenerative ocular pathologies based on these structural and organizational changes. In this project, (1) we will implement a prototype a/LCI system to enable in vivo studies of the retina and (2) apply the system to a detailed time course study of a murine model of progressive retinal degeneration to characterize the changes in both size and organization of photoreceptor structures as a function of disease progression. Upon successful completion of this exploratory research study, there will be justification to pursue development of a clinical a/LCI device for application to humans.